Relationship among alpha-synuclein accumulation, dopamine synthesis, and neurodegeneration in Parkinson disease substantia nigra.

The histologic hallmark of Parkinson disease (PD) is loss of pigmented neurons in the substantia nigra (SN) and locus ceruleus (LC) with accumulation of alpha-synuclein (alphaS). It has been reported that tyrosine hydroxylase (TH)-negative pigmented neurons are present in these nuclei of patients with PD. However, the relationship between TH immunoreactivity and alphaS accumulation remains uncertain. We immunohistochemically examined the SN and LC from patients with PD (n = 10) and control subjects (n = 7). A correlation study indicated a close relationship among decreased TH immunoreactivity, alphaS accumulation, and neuronal loss. In addition, 10% of pigmented neurons in the SN and 54.9% of those in the LC contained abnormal alphaS aggregates. Moreover, 82.3% of pigmented neurons bearing alphaS aggregates in the SN and 39.2% of those in the LC lacked TH immunoreactivity, suggesting that pigmented neurons in the SN have a greater tendency to lack TH activity than those in the LC. Recent studies have shown that this decrease of TH activity leads to a decrease of cytotoxic substances and that decreased dopamine synthesis leads to a reduction of cytotoxic alphaS oligomers. Therefore, the decrease of TH immunoreactivity in pigmented neurons demonstrated here can be considered to represent a cytoprotective mechanism in PD.

Hypoglycemic encephalopathy with extensive lesions in the cerebral white matter.

Here we report an autopsy case of hypoglycemic encephalopathy with prolonged coma. Laboratory data obtained when the patient lapsed into a coma showed that she had a low level of serum glucose (27 mg/dL). Although the level of glucose returned to within the normal range rapidly after glucose infusion, the patient remained in a coma for 22 months. It was presumed that the state of hypoglycemia persisted for about 4 h. There was no evidence of hypotension or hypoxia. Magnetic resonance imaging was performed 3 h after glucose administration; diffusion-weighted images revealed hyperintensity in the cerebral white matter and in the boundary zone between the middle and posterior cerebral arteries. Post-mortem examination revealed superficial laminar necrosis throughout the cerebral cortex. Neuronal necrosis was also found in the hippocampus and dentate gyrus, although the CA3 region appeared normal. In addition to these lesions, which are consistent with hypoglycemia-induced brain damage, the cerebral white matter exhibited severe loss of myelin and axons with reactive astrocytosis and macrophage infiltration. Old infarcts were also present in the bilateral occipital lobes. Since the cerebral blood flow is reported to be decreased during severe hypoglycemia, the present findings suggest that white matter lesions and boundary-zone infarctions may develop primarily in uncomplicated hypoglycemia.

Oligodendrocytes within astrocytes ("emperipolesis") in the cerebral white matter in hepatic and hypoglycemic encephalopathy.

We report the occurrence of oligodendrocytes within astrocytes ("emperipolesis") in two autopsy cases of metabolic encephalopathy: one patient with hepatic encephalopathy due to citrullinemia who suffered recurrent unconsciousness (clinical duration, 32 months) and another with hypoglycemic encephalopathy who lapsed into a persistent vegetative state (clinical duration, 22 months). In both cases, hypertrophic astrocytes were found to have engulfed one to several oligodendrocytes in the devastated cerebral white matter. Previous studies have reported that emperipolesis occurs in various CNS diseases showing destruction of myelin or inflammation of the white matter, including multiple sclerosis, cerebral infarct and CJD. The present findings suggest that emperipolesis can occur even in chronic metabolic disorders that extensively involve the cerebral white matter.

Disseminated intraparenchymal microgranulomas in the brainstem in central nervous system sarcoidosis.

We report a 70-year-old woman with sarcoidosis and multiple cranial nerve palsy. The patient suffered from dysarthria, dysphagia and weakness of the upper and lower extremities and died of sepsis. No abnormalities were noted in brain MRI. At autopsy, numerous epithelioid granulomas with Langhans giant cells were present in the bilateral lungs, including the hilar lymph nodes. The brain had a normal external appearance. Histologically, there were brainstem parenchymal lesions consisting of many microgranulomas, lymphocytic infiltration, activated microglias and astrocytosis. Perivascular lympocytic cuffing was also seen. Neither granulomas nor lymphocytic infiltration were seen in the leptomeninges. The present case was considered to be a peculiar type of neurosarcoidosis, that is, "sarcoid brainstem encephalitis".

An autopsy case of early ("minimal change") olivopontocerebellar atrophy (multiple system atrophy-cerebellar).

We report a 57-year-old woman with multiple system atrophy (MSA) of 15-month duration. The patient developed dysarthria, followed by impaired balance of gait, mild limb ataxia, and saccadic eye movement. A postmortem examination performed after she was found dead in a bathtub revealed neuronal loss restricted to the olivopontocerebellar system, being more severe in the pontine nucleus. Mild neuronal loss was also found in the anterior vermis and inferior olivary nucleus. Alpha-synuclein immunohistochemistry demonstrated widespread occurrence of glial cytoplasmic inclusions in the central nervous system, which were more numerous in the pontine base and cerebellar white matter. In contrast, neuronal alpha-synuclein accumulation was confined to the pontine and inferior olivary nuclei. The number of neuronal intranuclear inclusions was much higher than that of neuronal cytoplasmic inclusions. Moreover, alpha-synuclein accumulation was more severe in the neurites than in the cytoplasm or nucleus. This case demonstrates the early pattern of brain pathology in MSA-cerebellar (olivopontocerebellar atrophy).

Peculiar venous lesions in fatal hyponatremic brain edema.

A 19-year-old woman with a 3-year history of schizophrenia suddenly began to vomit, and rapidly developed a coma an hour after the onset of vomiting. A brain CT scan showed diffuse brain edema with compression of the ventricles. Laboratory tests showed a low serum sodium concentration of 117 mmol/L. She died 67 h after the onset of the first symptom. A postmortem examination showed diffuse swelling of the brain with bilateral uncal and tonsillar herniations. Histologically, no necrotic, hemorrhagic or encephalitic changes were seen. However, microvacuolar changes with lymphocytic infiltration were found in the venous walls (media and adventitia) mainly in the basal ganglia, thalamus and brainstem. To our knowledge, this is the first demonstration of venous alterations in fatal hyponatremic brain edema. These changes may have participated in the exacerbation of the brain edema due to functional disturbance of venous drainage.

Multinucleated astrocytes in old demyelinated plaques in a patient with multiple sclerosis.

A 51-year-old woman with MS of 26 years duration is reported. The patient's MS history began at the age of 25 years with an initial relapsing-remitting course, followed by slow progression without distinct relapses. She became bed-ridden at the age of 40 years. A post-mortem examination revealed numerous demyelinated plaques that exhibited fibrillary gliosis with Rosenthal fibers, but without lymphocytic cuffing or foamy macrophages. Activated microglia were found mainly in the marginal portion of the plaques. These plaques were consistent with so-called 'slowly expanding plaques'. Interestingly, multinucleated astrocytes were observed within the plaques, being more numerous in the area where microglial infiltration had occurred. These findings suggest that mild persistent inflammatory processes are present even in old plaques and that certain inflammatory stimuli cause multinucleation of astrocytes. This might explain the gradual deterioration without definite relapses observed in the late stage of MS.

Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy.

We immunohistochemically examined the brain and peripheral sympathetic ganglia from eight patients with multiple system atrophy (MSA), using an antibody specific for phosphorylated alpha-synuclein (anti-PSer129). Phosphorylated alpha-synuclein was deposited in five cellular locations: oligodendroglial cytoplasm and nucleus, and neuronal cytoplasm, processes and nucleus. Many neuronal cytoplasmic inclusions (NCIs) were found in the pontine and inferior olivary nuclei and, to a lesser extent, in the substantia nigra, locus ceruleus, and neocortical and hippocampal neurons. NCIs were also found in the sympathetic ganglia in two out of the eight cases. Moreover, anti-PSer129 immunohistochemistry revealed extensive neuropil pathology; swollen neurites were abundant in the pontine nucleus, delicate neurites were observed in the deeper layers of the cerebral cortex and thalamus, and neuropil threads and dot-like structures were distributed in the basal ganglia and brainstem. Diffuse neuronal cytoplasmic staining (pre-NCI) was frequently found in the pontine and inferior olivary nuclei. Thus, the widespread accumulation of phosphorylated alpha-synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA.

Hydranencephaly with extensive periventricular necrosis and numerous ectopic glioneuronal nests.

The case reported here relates to a male infant with hydranencephaly who was born at 37 weeks of gestation and died immediately after birth. Post-mortem examination revealed that the cerebral hemispheres had been replaced by fluid-filled cavities within a normal-sized cranium. The membranous hemispheric wall was composed of gliosed tissue with multiple foci of necrosis and hemosiderin-laden macrophages. The ependyma was absent. Many necrotic foci containing hemosiderin were also found around the aqueduct and fourth ventricle. These findings suggest that hemorrhagic necrosis had occurred throughout the periventricular region, and more severely in the cerebral hemispheres. Moreover, numerous glioneuronal nests were found throughout the subarachnoid space and ventricles. Glioneuronal nests, if present, are usually minimal in hydranencephaly, whereas it is one of the pathological features of multicystic encephalopathy. The transition of multicystic encephalopathy to hydranencephaly has been demonstrated repeatedly. The former is a condition resulting from a severe circulatory disturbance, most often at the end of gestation or in the perinatal period. These lesions date later than hydranencephaly. Considering that numerous glioneuronal nests were found in the present case, it is likely that the encephaloclastic process developed toward the end of gestation.

[Epstein-Barr virus-associated encephalitis presenting as refractory status epilepticus that persisted for nearly 2 months with excellent recovery].

A 37-year-old woman presented with Epstein-Barr virus (EBV)-associated encephalitis that developed into refractory status epilepticus ten days after the onset of headache and fever, without signs suggestive of infectious mononucleosis. An electroencephalogram showed definite epileptogenic changes, including diffuse slow wave bursts with paroxysmal generalized bilateral sharp waves. The patient required general anesthesia for nearly two months, but had completely improved 18 months later. The patient developed Klüver-Bucy syndrome four months after the onset: bilateral frontal hypoperfusion was detected with SPECT at this time, but also improved after 18 months. MRI showed a 2-3 mm lesion of the cerebellar white matter, which was suggestive of a small demyelinaed focus. The patient's serum was positive for EBV DNA within two weeks of onset, but negative there-after. However, the CSF was positive for EBV DNA for more than five months, with a four-fold increase in the titers of IgG antibody for EBV-viral capside antigen in the CSF. Given the patient's good recovery from her critical condition, her severe encephalitis/encephalopathy with persistent status epilepticus probably resulted from an EBV-associated immune-response after the reactivation of EBV, rather than from a direct infiltration of EBV into the brain.

Reciprocal accumulation of beta-synuclein in alpha-synuclein lesions in multiple system atrophy.

Alpha-Synuclein is a major component of neuronal and glial cytoplasmic inclusions in multiple system atrophy (MSA), one of the alpha-synucleinopathies. Recent studies have shown that beta-synuclein, a homolog of alpha-synuclein, inhibits alpha-synuclein aggregation in vitro. We immunohistochemically examined the MSA brain, using specific antibodies against alpha-synuclein and beta-synuclein. alpha-synuclein-positive filamentous aggregates were frequently found in neurons in the pontine and inferior olivary nuclei. No abnormal accumulation of alpha-synuclein was noted in Purkinje cells. In contrast, beta-synuclein accumulation occurred extensively in Purkinje cells, and only minimally in pontine and olivary neurons. Thus, neuronal alpha-synuclein inclusions appear to occur only rarely in neurons in which beta-synuclein accumulates. These findings support the possibility that beta-synuclein is a negative regulator of alpha-synuclein aggregation.

Posterior encephalopathy subsequent to cyclosporin A presenting as irreversible abulia.

A case of cyclosporin A (Cys A)-induced posterior encephalopathy developed into persistent abulia despite rapid and marked improvement of abnormal T2- and FLAIR MRI hyperintense regions. Diffusion-weighted MRI signal intensity was also high at the onset. This change is atypical in Cys A-induced encephalopathy and was thought to predict poor recovery from the encephalopathy. Persistent abulia was probably due to marked hypoperfusion in the whole cortex including bilateral frontal lobes and basal ganglia as detected by SPECT. Apart from the breakdown of the blood-brain barrier, direct toxicity of Cys A to the brain may play a role in the pathogenesis of chronic, irreversible encephalopathy.

Acute cholecystitis and duodenitis associated with Churg-Strauss syndrome.

We describe a patient with acute cholecystitis and duodenitis associated with Churg-Strauss syndrome. A 36-year-old male, who had been healthy, had abdominal pain following high fever. He had marked hypereosinophilia of 17,000/mm3. Radiographs of the chest disclosed a transient infiltrated lesion in the left lower lung. Ultrasonographic and gastroendoscopic examinations revealed acute cholecystitis and duodenitis, respectively. Endoscopic retrograde cholangiopancreatography demonstrated a filling defect suspecting aberrant ascariasis in the common bile duct. The patient suddenly developed distally dominant mononeuritis multiplex, especially in the upper limbs. Muscle biopsy revealed vasculitis of intramuscular arteries with infiltration of eosinophils. These findings fulfilled the diagnostic criteria of Churg-Strauss syndrome. Corticosteroid dramatically resolved the abdominal symptoms. Cholecystectomy and removal of the foreign body were performed. Histological examinations revealed that necrosis of the gallbladder was caused by occlusion due to thrombosed arteries and that the foreign body in the common bile duct was an aggregate of necrotic epithelium of the bile duct wall surrounded by inflammatory cells. Although abdominal complaints rarely appeared as an initial symptom in the patients with Churg-Strauss syndrome, this syndrome should be taken into consideration for an accurate diagnosis when the patients with abdominal pain of unknown origin had eosinophilia, asthma, or allergic rhinitis.

[A case of Fisher's syndrome after Haemophilus influenzae infection].

We report a case of Fisher's syndrome with serological evidence of antecedent Haemophilus influenzae infection. A 66-year-old woman developed unsteady gait and multiple cranial nerve palsies after upper respiratory infection. Serum anti-GQ 1 b and anti-GT 1 a IgG antibodies were positive. In the acute phase of the illness, her serum had high titers of IgM, IgG and IgA anti-H. influenzae antibodies, which significantly decreased during the clinical course. Further study is needed to clarify the clinical and immunological features of Fisher's syndrome after H. influenzae infection.

Generation of symptomatic palatal tremor is not correlated with inferior olivary hypertrophy.

Although the generation of symptomatic palatal tremor (SPT) is thought to derive from the abnormal activity of hypertrophic inferior olivary neurones, the actual mechanism of SPT has not yet been elucidated. We therefore investigated the relationship between SPT and the pathological process of inferior olivary hypertrophy (IOH). We examined 16 autopsied subjects with cerebrovascular lesions of the dentate-olivary tracts. We analysed the size of the olives, the number of olivary neurones, synaptic, axonal and astrocytic changes in the olives and the clinical course in the subjects. SPT was observed in eight patients, in seven of whom it appeared 1-2 months after interruption of the afferents then progressed to reach a peak approximately 1-2 years from the onset. SPT persisted for the rest of the subjects' lives without decreasing in severity. Neuronal hypertrophic change began 20-30 days after the onset of the causative lesions and reached maximum size, accompanied by prominent astrocytosis and synaptic and axonal remodelling, 6-7 months later. The number of olivary neurones decreased to <10% of that in controls in patients who survived >6 years. Despite the persistence of SPT, both the myelin and the axons of efferent fibres from olivary neurones were severely degenerated in patients who survived several years. Therefore, the appearance of SPT may depend on the hyperactivity of olivary neurones released from inhibitory inputs until the peak of both IOH and SPT. However, the persistence of peak intensity and distribution of established SPT is probably due to both the disturbance of natural rhythmicity in the body and the lack of feedback from the abnormal movement resulting from the dysfunction of the olive.